The cell - DOC by maclaren1

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									                         CELL PHYSIOLOGY
                STRUCTURE AND FUNCTION OF THE CELL

Elementary construction unit of all live organisms.
          Protocellular organisms
          Procaryotic cells
          Eucaryotic cells - DNA is kept in a compartment separate from the cytoplasm
            cytoplasm contains distinctive organelles (rich array of internal membranes, chloroplasts and
               mitochondria - both are thought to have a symbiotic origin)
            have a cytoskeleton (actin filaments and microtubules)
In the multicellular organisms:
    1. cells become specialized and cooperate
    2. cells posses higher hereditary information
    3. multicellular organization depends on cohesion between cells and cell recognition
    4. cell memory permits the development of complex patterns
    5. a complex machinery for reproduction evolves

Cellular development
   1. Arise by proliferation - "omnis cellula e cellula"
   2. Growth and development - differentiation (nerve cells)
   3. Period of function
   4. Senescence - accumulation of catabolytes, errors in transcription and translation, changes in colloids -
      disintegration, death of the cell
   Cells with short half time - quick replacement - blood cells, epithels
   Cells with long half time (or without further multiplication) - adipose cells, glial cells, neurons, muscle
      cells


                 PRINCIPAL CELL ORGANELLES

The membranous structures of the cell:
        All cell organelles are lined by membranes composed primarily of lipids and proteins. The lipids of
the membrane provide a barrier that prevents free movements of water and water soluble substances from
one cell compartment to the other. The protein molecules in the membrane, on the other hand, often
penetrate all the way through the membrane, thus interrupting the continuity of the lipid barrier, and
therefore provide pathways for passage of specific substances through the membranes. Also many of the
membrane proteins are enzymes that catalyze a multitude of different chemical reactions.

The cytoplasm
         Colloid solution within the cell, where other organelles are dispersed.
(actually a very complex system of spaces, membranous walls, filaments and tubules - with attached other
organelles)

The Endoplasmic Reticulum
         A network of tubular and flat vesicular structure. Individual elements are interconnected with each
other. Their walls are constructed of the lipid bilayer and contain large amounts of proteins. In some cells
(e.g. liver cells) the total surface area of endoplasmic reticulum is 30 to 40 times as great as the cell plasma
membrane area.
         The space inside the tubules and vesicles is filled with endoplasmic matrix, a fluid medium, which is
different from the fluid outside the endoplasmic reticulum Space inside the endoplasmic reticulum is
connected with the space between the two membranes of the double nuclear membrane. It often occupies
more than 10% of the total cell volume.
         The vast surface area of the endoplasmic reticulum, containing multiple enzyme systems, provides
the machinery for most of the metabolic functions of the cell.
         Attached to outer surfaces of many parts of the endoplasmic reticulum are large numbers of
ribosomes - granular endoplasmic reticulum. The ribosomes have an essential role in the synthesis of
proteins.
         Part of the endoplasmic reticulum has no attached ribosomes - that part is called agranular, or
smooth endoplasmic reticulum. It functions in the synthesis of lipid substances (e.g. it predominates in cells
that synthesize steroid hormones, hepatocytes - lippoproteins) and in many other enzymatic processes of the

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cell. In striated muscles the agranular endoplasmic reticulum is related to the mechanism of contraction
(calcium ions are stored there).

Golgi apparatus
         Golgi apparatus is closely related to the endoplasmic reticulum, usually located near the nucleus. It
has membranes similar to those of the agranular endoplasmic reticulum. It is usually composed of four or
more stacked layers of thin, flat enclosed vesicles lying near the nucleus. Swarms of small vesicles (50 nm in
diameter) are often associated with the main cistern. This apparatus is very prominent in secretory cells, in
these cells it is located on the side of the cell from which the secretory substances are extruded.
        The Golgi apparatus functions in association with the endoplasmic reticulum. Proteins, synthesized
in endoplasmic reticulum are stored in Golgi apparatus and some of them are bonded to some carrier (e.g.
glycoprotein for hypophyseal hormones). Small "transport vesicles" (ER vesicles) continually pinch off the
endoplasmic reticulum and shortly after fuse with Golgi apparatus. In this way, substances are transported
from endoplasmic reticulum to Golgi apparatus.

The Lysosomes
        Lysosomes are vesicular organelles formed by the Golgi apparatus that then become dispersed
through the cytoplasm. In some cell are very numerous and are visible in LM (granules in granulocytes,
osteclasts). The lysosomes provide an intracellular digestive system that allows the cell to digest and thereby
remove unwanted substances and structures, especially damaged and foreign structures, such as bacteria,
complexes antigen-antibody. They differ from one cell to another, but usually they are 250-750 nm in
diameter. They are surrounded by typical lipid bilayer membrane and contain protein aggregates of
hydrolytic (digestive) enzymes. (Hydrolytic enzymes are capable of splitting organic compounds by
combining hydrogen from water molecule with part of the compound and by combining the hydroxyl portion
of the water molecule with the other part of the compound. E.g., protein is hydrolyzed to form amino acids,
glycogen is hydrolyzed to form glucose.) More than 50 different acid hydrolases were found in lysosomes,
and principal substances that they digest are proteins, nucleic acids, mucopolysaccharides, lipids and
glycogen.
        The lysosomes often contain bactericidal agents (lysozyme) that can kill phagocytized bacteria
before they can cause cellular damage.
        Ordinarily, the membrane surrounding the lysosomes prevents the enclosed enzymes from coming in
contact with other substances in the cell. However, many different conditions of the cell may break the
membrane of the lysosomes, allowing release of the enzymes. The enzymes then split the organic substances
within the cell - one of the mechanisms of cell death (hypoxia, action of some toxins, Ca2+).

The Peroxisomes
         Peroxisomes are similar to lysosomes., but they are different in two important ways: They are
believed to be formed by splitting from the smooth endoplasmic reticulum, rather than from Golgi apparatus.
         They contain oxidases rather than hydrolases. Oxidases are capable to form hydrogen peroxide,
which together with catalase, also present in peroxisomes, can oxidase many substances, that otherwise
might be poisonous to cell (e.g. most of the alcohol that a person drinks is detoxified by the peroxisomes of
the liver cells).

Secretory vesicles
        Almost all secretory substances are formed by the endoplasmic reticulum - Golgi apparatus and then
released from Golgi apparatus into the cytoplasm in the form of storage vesicles (also secretory vesicles or
secretory granules). (E.g. in pancreas, secretory vesicles inside pancreatic acinar cells store protein
proenzymes, that are secreted later through the cell membrane into the pancreatic duct).

The Mitochondria
         The "Powerhouses" of the cell. These organelles are present in essentially all parts of the cell. The
total number per cell varies form less than hundred up to several thousand, depending on the amount of
energy required by each cell. Furthermore, mitochondria are concentrated in those portions of the cell that
are responsible for the major share of its energy metabolism (e.g. synapses). Mitochondriae are very variable
in size and shape (globular, filamentous, branching).
         Mitochondriae are composed mainly of the two lipid bilayer-protein membranes (cristae) - an outer
membrane and an inner membrane. Many infoldings of the inner membrane form shelves into which
oxidative enzymes are attached. Matrix of the mitochondrion contains also large quantities of dissolved
enzymes. Enzymes of mitochondria are necessary for extracting energy form nutrients - oxidation of
nutrients - forming carbon dioxide and water. The liberated energy is used to synthesize a high-energy
substance called adenosine triphosphate. ATP is then transported out of the mitochondriae and diffuses
through the cell. The enzyme pattern is not identical in all mitochondria. There is a profound specialization

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of these organelles (liver, brown fat). The enzymatic equipment differs also during the ontogenesis
(mitochondria in newborn brain are less sensitive to hypoxia than the adult ones).
         Mitochondriae are self-replicative, which means that one mitochondrion can form a second one
whenever there is need in the cell for increased amounts of ATP. Mitochondriae have non-Mendelian
(cytoplasmic) inheritance (all mitochondria are maternally inherited). Mitochondriae show many similarities
to free-living procaryotic organisms, they contain DNA, ribosomes, they make protein, they reproduce.
Without mitochondriae the cells of animals and fungi would be anaerobic organisms, depending on the
relatively inefficient process of glycolysis  Eucaryotic cells are descendants of primitive anaerobic
organisms that survived, in a world that had became rich in oxygen, by engulfing aerobic bacteria. The
eucaryotic plasma membrane therefore needn't maintain a large H+ gradient, as required for ATP production.
It evolved instead an elaborate system of control of the ion permeability for transmembrane transport and
cell signaling purposes. It appears that mitochondriae are descendants of a particular type of purple
photosynthetic bacterium, which had previously lost its ability to carry out photosynthesis and was left with
only a respiratory chain.
  (Chloroplasts in plant cells are descendants of cyanobacteria)

Filament and Tubular Structures of the Cell
        The fibrillar proteins of the cell are usually organized into filaments or tubules. The primary
function of these organelles is to act as cytoskeleton, providing rigid structures for certain parts of the cell.
They can be also the source of cell movements and movements of the compound inside the cell.

The Nucleus
         The nucleus is called "The Control center of the cell". The n. contains large quantities of DNA.
DNA determines:
  1. the characteristics of the proteins of the cytoplasm
  2. the individual set of proteins in each type of cell
  3. the reproduction of the cell
         In L.M. and E.M. DNA visible as chromatin, during mitosis chromatin material becomes organized
into chromosomes.
         The nuclear envelope (not correctly the nuclear membrane) consists of two separate membranes: the
outer membrane is continuous with endoplasmic reticulum and the space between the two nuclear
membranes is continuous with the compartment inside the endoplasmic reticulum. The nuclear envelope is
penetrated by several thousands nuclear pores. These are very large, almost 100 nm in diameter, but because
of various protein complexes attached around the edges of the pores, the effective area of the pore is only
about 9 nm in diameter. This size is large enough to allow molecules up to 44,000 molecular weight to pass
through. The nuclear envelope is designed to shield the contents of the nuclear compartment from many of
the particles, filaments and large molecules that function in the cytoplasm. Larger molecules, needed for the
function of nucleus (e.g. DNA and RNA polymerases) interact with receptor proteins located on the pore
margin and are actively transported (translocated) into the nucleus.

The Nucleolus
        The nuclei of most cells contain one or more nucleoli. They are unique because of the lack of a
limiting membrane. It is simply an accumulation of RNA and proteins within the nucleus. The nucleolus
becomes considerably enlarged when a cell is actively synthesizing proteins. RNA, synthesized in the
nucleus loose its fibrillar structure in the nucleolus and later condenses into granular units of ribosomes.
These are transported through the nuclear membrane pores into the cytoplasm, where they assemble together
to form the mature ribosomes, either in the cytosol, or in association with the endoplasmic reticulum

The Ribosomes
        Majority is attached to the outer list of the membrane of endoplasmic reticulum, part is dispersed in
the cytoplasm. They contain RNA (ribosomal RNA) and are important for the synthesis of proteins.


                PLASMA MEMBRANE

   1. encloses every cell and defines the its extent
   2. builds and maintains the essential differences between its content and environment
   3. participates in cell communication (membrane bound or released signaling molecules, receptors,
      signal transmission machinery)
thickness 7-10 nm, high electric resistance, low permeability, morphological and functional asymmetry


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Membrane lipids
50% of the mass of most animal cell plasma membranes
approximately 5x106 lipid molecules per 1m2
three major types: phospholipids, cholesterol, glycolipids
amphiphilic (amphipathic) properties = polar (hydrophilic) and nonpolar (hydrophobic) end
phospholipid molecule:
    polar head group (glycerol, phosphate, alcohol: choline, ethanolamine, or amino acid)
    two hydrophobic hydrocarbon tails -
         tails can differ in length (usually 14 and 24 carbon atoms), one tail has usually one or more cis-double
         bounds (it is unsaturated). Unsaturated bond creates a small kink in the tail. Differences in tail length
         and shape influence the ability of phospholipid molecules to pack against one another and thereby
         affect the fluidity of the membrane
Most of the amphiphilic molecules in an aqueous environment tend to form spontaneously either bilayer or
    spherical micelles  lipid bilayers tend to reseal themselves when they are torn.
Individual lipid molecules can move within the bilayer:
    lateral movements within the monolayer - very frequent
    flip-flop movements across the bilayer - very restricted
The fluidity of a lipid bilayer depends on its composition:
    a shorter chain length reduces the tendency of hydrocarbon tails to interact with another
    cis-double bonds make the hydrocarb. tails more difficult to pack together
    cholesterol molecules (in eucaryotic cell up to one molecule of cholesterol for every phospholipid
         molecule) - orient within the lipid layer:
             steroid rings interact with hydrocarbon chains - immobilize the movements of tails to heads
             decrease the permeability of lipid bilayer to small water-soluble molecules
The fluidity of plasma membrane is biologically important - e.g., some specimens (procaryotic) can change
    the chemical composition of lipids according to the temperature of their environment (concentration of
    fatty acids with double-bonds).
The lipid bilayer serves as a solvent for membrane proteins:
    membrane is a two dimensional solvent for proteins, composition of phospholipids (size, shape and
    charge of their heads) is important for the function of protein molecules embedded into it - some proteins
    can function only in the presence of specific phospholipid head groups.
The lipid bilayer is structurally asymmetrical. Functional asymmetry results mainly of membrane protein
arrangement.
  1. different phospholipids (negatively charged phosphatidylserine is more frequent in the inner monolayer)
      - inner monolayer is more negatively charged
  2. different distribution of fatty acid tails - inner monolayer is more fluid than outer
  3. glycolipids are present only in the outer monolayer and their sugar groups are exposed at the cell
      surface, some of them may act as cell-surface receptors or some may have antigenic properties

Membrane proteins
         Most of the specific functions of biological membranes are carried out by proteins (less than 25% of
the membrane mass in myelin, 75% in mitochondrial membrane, 50% average, lipids are small - 50 lipid
molecules per 1 molecule of protein). They serve as specific receptors, enzymes, transport proteins.
Most of the membrane proteins are aphilitic (transmembrane, integral membrane proteins):
  1. hydrophobic region that pass through the membrane and interacts with hydrophobic tails of lipid
     molecules - covalently attached to lipid molecules
  2. hydrophilic regions are exposed to water on one ore both sides of the membrane
         A transmembrane protein always has a unique orientation in the membrane. It reflects the functional
differences of its cytoplasmic and extracellular domains. Some of the proteins are bound only to
transmembrane proteins (peripheral membrane proteins) by noncovalent interactions
Spectrin - peripheral protein of the cytoplasmic side (erythrocytes) - principal component of the
    cytoskeleton - one of the contractile proteins (enables the red blood cells to withstand the stress on its
    membrane as they are forced through narrow capillaries)
Ankyrin - responsible for binding the spectrin cytoskeleton to the plasma membrane, similar protein can
    anchor proteins of ion channels in certain domains of the plasma membrane
Glycophorin - small transmembrane glycoprotein, in red blood cells covers majority of the surface and is
    responsible for most of the negative charge of the surface. Similar glycoproteins in other kinds of cells act
    as cell surface receptors.
Transport and channel proteins
Receptor proteins


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Membrane carbohydrates
All eucaryotic cells have carbohydrate on their surface, forming 2-10% of membrane's total weight.
    oligosaccharide and polysaccharide chains covalently bound to membrane proteins
    oligosaccharide chains covalently bound to lipids (glycolipids)
    carbohydrates are confined mainly to noncytosolic surface of membranes (outer lipid monolayer in
        plasma membrane)
    some proteoglycans (long polysaccharide chains linked to a protein core) extend across the lipid bilayer
    cell coat, glycocalyx - carbohydrate rich peripheral zone on the outside surface of most eucaryotic cells
          The complexity of membrane carbohydrate molecules, together with their exposed position on the
cell surface, suggests that membrane carbohydrates may play an important part in cell to cell recognition
processes.


                         FUNCTIONAL SYSTEMS OF THE CELL

Ingestion by the cell - endocytosis
         Substances for the life and growth of the cells are obtained from the surrounding fluids. They pass
through the cell membrane by diffusion and active transport. Larger particles enter the cell by a specialized
function of the cell membrane, called endocytosis. Two principal forms of endocytosis are pinocytosis and
phagocytosis.
         Pinocytosis ("cellular drinking") means ingestion of extremely small vesicles containing
extracellular fluid. It occurs at all cell membranes, but it is highly developed in some cells (in the
macrophages about 3% of the total surface membranes is engulfed in the form of vesicles each minute) and
is sometimes higher at specialized regions of the plasma membrane. Pinocytosis is the only mean by which
very large molecules can enter cells (e.g. cholesterol together with low-density lipoproteins). The rate of
pinocytosis is enhanced when such macromolecules attach to the cell membrane.
         Molecules of protein attach to the membrane. These molecules usually bind to receptors that are
specific for the types of proteins that are to be absorbed, receptors are usually concentrated in small pits in
the cell membrane, called coated pits. On the inside of the cell membrane beneath these pits is a latticework
of fibrillar protein and some contractile filaments (coat-associated proteins: clathrin, actin and myosin-like
proteins). Once the protein has bound with the receptors, the entire pit invaginates inward and the contractile
proteins cause its borders to close over the attached proteins. The invaginated portion of the membrane then
breaks away from the surface of the cell and forms a pinocytic vesicle, coated vesicle. This process requires
energy (ATP) and presence of calcium.
         Phagocytosis means ingestion of larger particles, such as bacteria, cells, or portions of degenerating
tissue. Only certain types of cells have the capability of phagocytosis (most notably the tissue macrophages
and some white blood cells).
         Phagocytosis is initiated when proteins of large polysaccharides on the surface of the particle bind
with receptors on the surface of the phagocyte. In case of bacteria, these usually are attached to specific
antibodies and the antibodies in turn attach to the phagocyte receptors (opsonization - flavouring). The edges
of the membrane around the attachment evaginate outward to surround the particle, then more and more
membrane receptors attach to the particle ligand until the particle is completely surrounded (membrane-
zippering mechanism). Actin and other contractile fibrils in the cytoplasm surround the engulfed particle and
contract, pushing the object further to the interior.
         Both pinocytic and phagocytic vesicles turn into endosomes. These are vesicles with high H+ content
(result of ATP driven H+ pump). Most of the content ends up in lysosomes. However, many molecules (e.g.
ligand-receptor complexes, transferrin) are recycled from endosomes to the plasma membrane via specific
transport vesicles that bud off from these endosomes. Recycling of membrane receptors is part of the
receptor regulation (receptor down-regulation).
         Some receptors on the surface of epithelial cells transfer specific macromolecules from one
extracellular space to the other by a process called transcytosis (newborn rat - antibodies from its mother's
milk).

Digestion of foreign substances in the cell
        Almost immediately after a pinocytic of phagocytic vesicle appears inside a cell, one or more
lysosomes become attached to the vesicle and empty their enzymes into the vesicle. Thus a digestive vesicle
is formed. Hydrolytic enzymes then break proteins, glycogen, nucleic acids, mucopolysaccharides and other
substances in the vesicle. The products of digestion (amino acids, glucose, phosphate) diffuse through the
membrane into the cytoplasm. What is left is called a residual body, and is finally excreted through the cell
membrane by the process called exocytosis, which is essentially the opposite of endocytosis.
        In certain conditions, tissues of the body regress to smaller size (uterus after pregnancy, muscles
during inactivity, mammary glands after the period of lactation). Lysosomes are responsible for much of this

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regression. The removal of damaged cells is another special role in which phagocytosis and lysosomes are
involved.

Synthesis and formation of cellular structures
          Most of the synthesis begins in the endoplasmic reticulum, but most of the products are then passed
on to the Golgi apparatus, where they are further processed and released into the cytoplasm. In the granular
endoplasmic reticulum protein molecules are synthesized within the ribosomes. The ribosomes then extrude
most of the synthesized protein into the matrix of endoplasmic reticulum. Almost all protein molecules are
then glycosylated, that is conjugated with carbohydrate moieties to form glycoproteins. Proteins which do
not enter endoplasmic reticulum but are extruded into cytosol are mainly free proteins.
          Some proteins can move between the cell compartments through individual membranes. It requires a
special protein translocator in the membrane, which carries the protein through (translocation of proteins
from ribosomes into endoplasmic reticulum).
          Lipids, especially phospholipids and cholesterol are synthesized in the smooth endoplasmic
reticulum. They are rapidly incorporated into the lipid bilayer of endoplasmic reticulum, thus causing it to
grow continually. To keep the size of endoplasmic reticulum, small vesicles called endoplasmic reticulum
vesicles, or transport vesicles, continually break away and migrate to the Golgi apparatus.
          In Golgi apparatus the synthesis of certain carbohydrates can be present. E.g. very large saccharide
polymers bound with only small amounts of proteins: hyaluronic acid and chondroitin sulphate. They are
then the major components of the mucus and other glandular secretions, the major ground substance in the
interstitial spaces and the principal component of the organic matrix in both cartilage and bone.
          As substances are formed in endoplasmic reticulum, especially the proteins, they are transported
through the tubules toward the portions of the smooth endoplasmic reticulum that lie nearest to Golgi
apparatus. At that point, small transport vesicles of smooth endoplasmic reticulum break away and diffuse to
the deeper layers of Golgi apparatus. They instantly fuse with Golgi apparatus and empty their content into
vesicular space. Here, additional molecules can be added to the secretions. From the outermost layers of the
Golgi apparatus both small and large vesicles continually brake away, and diffuse through the cell. Using
radioactive labeling we can see that the newly formed protein molecules can be detected in the granular
endoplasmic reticulum within 3-5 min, in 20 min the newly formed proteins are present in Golgi apparatus
and after 1-2 hours they are secreted from the surface of the cell.
          Secretory vesicles empty their content to the exterior by a mechanism of exocytosis. It is essentially
the opposite of endocytosis. It requires also the action of contractile proteins and the presence of calcium.
Some of the vesicles fuse with the cell membrane to replenish these membranes after the loss of its substance
during pinocytosis and phagocytosis.
          Lysosomes and peroxisomes are also formed in specialized portion of the Golgi apparatus or smooth
endoplasmic reticulum.

Extraction of energy from nutrients
       Function of the mitochondria

Motor activity of cells
       Function of the cytoskeleton

Development of cell organelles
        When a cell reproduces and divides, it duplicates its membrane-bounded organelles, which then
divide and are distributed to the daughter cells. Cells cannot make these organelles de novo. The information
required to construct a membrane-bounded organelle does not reside exclusively in the DNA of the nucleus.
Epigenetic information is also required (part of the cytoplasmic inheritance).


                                 MEMBRANE TRANSPORT

Membrane transport of small molecules
         Because of its hydrophobic interior, the lipid bilayer is a highly impermeable barrier to most polar
molecules. The rate at which a molecule diffuses across a lipid bilayer varies, depending largely on the size
of the molecule and its relative solubility in lipids. In general, the smaller the molecule and the more soluble
it is, the more rapidly it will diffuse across the bilayer. Water diffuses very rapidly, even though water
molecules are relatively insoluble in lipids. This is because water molecules have a very small volume and
are uncharged. In contrast, lipid bilayer is highly impermeable to all charged molecules (ions) - the charge
and high degree of hydration of such molecules prevents them from entering the hydrocarbon phase of the
bilayer.
      1. small nonpolar molecules (O2) diffuse rapidly across lipid bilayer membrane

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    2. small uncharged polar molecules (water, CO2, ethanol, urea) diffuse rapidly
    3. larger uncharged polar molecules (glycerol, glucose) diffuse slowly or hardly at all
    4. charged molecules (ions) - membrane is impermeable
         Cells have evolved special ways of transferring across their membranes (translocation) for those
water soluble molecules, which are necessary for their existence and at the same time membrane is
impermeable for them (ions, sugars, amino acids, nucleotides, metabolites).
         Different types of membrane translocation systems participate on the formation and maintenance of
the composition differences among the intracellular and extracellular fluid. Similar differences exist among
different intracellular compartments too (e.g. Ca++ content in the „cytoplasm“ and sarcoplasmic cisterns).
         Membrane transport proteins are responsible for transferring such substances, which are unable to
diffuse in a sufficient rate across cell membranes. Each protein is designed to transport a particular class of
molecule (ions, sugars, amino acids), or only certain species of the class. (Inherited disease cystinuria is
caused by inefficient transport mechanism for cystine from either urine or intestine with resulting
accumulation of cystine in the urine and formation of cystine "stones".) By forming a continuous pathway
across the membrane, membrane transport proteins enable the specific solutes they transport to pass across
the membrane without coming into direct contact with the hydrophobic interior of the lipid bilayer.

A. Channel proteins form water filled (aqueous) pores that extend across the lipid bilayer. They allow
   specific solutes (usually inorganic ions) to pass across the membrane. The rate of transfer via these
   systems can by high, effectively controlled, and not directly depending on the energy supply (passive
   transport of ions "down" their electrochemical gradients). Majority is ion selective - passing ion shed
   most of their associated water molecules and is recognized by its shape and charge in the narrowest part
   of the channel. Most of the channels are not continuously open - they have gates (gated channels).
B. Carrier proteins (carriers, transporters) transfer the solute across the bilayer by undergoing a reversible
   conformational change, that alternatively exposes the solute-binding site first on one side of the
   membrane and then on the other (Ping-Pong states).
   1. Many carrier proteins allow solutes to cross the membrane passively = passive transport, facilitated
      diffusion
Direction of diffusion is determined:
      In uncharged molecule - its concentration gradient
      In charged molecule - both concentration gradient and electrical potential difference across the
           membrane = electrochemical gradient
          All plasma membranes have an electrical potential difference across them, with the inside negative
compared to outside. This potential favors the entry of positively charged ions into cells but opposes the
entry of negatively charged ions.
          The process by which a carrier protein specifically binds and transfers a solute molecule across the
lipid bilayer resembles an enzyme-substrate reaction, and the carrier proteins behave like membrane-bound
enzymes:
    each type of carrier protein has a specific binding site for its solute (substrate)
    when carrier is saturated, the rate of transport is maximal
    transport rate is characteristic of the specific carrier
    the solute binding can be blocked by competitive inhibitors (which compete for the same binding site)
    in contrary to enzymes, carriers do not alter the molecules they interact with
Carrier proteins can have one or two types of binding sites:
   a) transport of a single solute from one side of the membrane to the other - uniport
   b) transfer of one solute depends on simultaneous or sequential transfer of a second solute
          ba) in the same direction - symport
          bb) in the opposite direction - antiport

   2. Active transport mediated by carrier proteins coupled to an energy source such as ATP hydrolysis, or
      an ion gradient:
Na+K+ATPase pump
         The pump operates as an antiport, actively pumping Na+ out of the cell against steep electrochemical
gradient and pumping K+ in.
Membrane bound carrier protein
   - has three receptor sites for binding Na+ on the portion of protein inside of the membrane
   - has two receptor sites for K+ on the outside
   - the inside portion has ATPase activity (ATP hydrolysis)


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         When three sodium ions bind on inside of the carrier protein and two potassium ions on the outside,
the ATPase becomes activated, cleaving one molecule of ATP liberates energy for a conformation change of
the carrier protein, extruding the sodium ions to the outside and the potassium ions to the inside.
   - present in all cell of the body
   - consumes about 1/3 of the energy required by the cell (2/3 in nerve cells)
Function:
 1. it causes ion gradients between the intracellular and extracellular solutions (K+ intracellulary, Na+
    extracellulary)
 2. driving three positively charged ions outside and only two inside the pump creates an electric potential
    with inside negative, relative to outside (directly contributes to the membrane potential - 10% =
    electrogenic effect, indirectly forms the whole potential difference)
 3. it controls the solute concentration inside the cell - regulates the osmotic forces - regulates the cell
    volume (inhibition of NaKATPase, e.g. with ouabain, causes swelling or even bursting of the cell)

Ca2+pump - similar function as the previous one
  Eucaryotic cells maintain very low concentrations of Ca2+ in their cytosol (approximately 10-7) in the face
      of very much higher extracellular Ca2+ concentration (approximately 10-3).
     2+
  Ca pump is a membrane-bound ATPase, which translocates two Ca2+ for every ATP molecule
      hydrolyzed:
        pumps Ca2+ outside the cell - cell membrane bound pump
        pumps Ca2+ into the sarcoplasmic reticulum of muscle cells (or similar organelles)

Enzymes that synthesize ATP
Membrane-bound enzymes that synthesize ATP are transport ATPases working in reverse. They are present
in the inner membrane of mitochondria (and in plasma membrane of bacteria). Instead of ATP hydrolysis
driving ion transport, ion flow (H+ gradient) across these membranes drive the synthesis of ATP from ADP
and phosphate. The H+ gradients are generated during the electron-transport steps of oxidative
phosphorylation.

Active transport driven by ion gradients
Many active transport systems are driven by the energy stored in ion gradients = secondary active transport)
- symports or antiports
- Na+ is usually cotransported - pump uses the electrochemical gradient of Na+
- energy is supplied by NaKATPase pump - primary active transport
  a) symport (cotransport) - transport of glucose, amino acids etc. in intestinal or in kidney epithelial cells
     (ability to transport glucose from the low concentration extracellular fluid to the comparatively high
     concentration in the intracellular fluid)
  b) antiport
     Na+-Ca2+ exchange - carrier removes excess of intracellular Ca2+ ions, usually as a result of previous cell
         signaling process
     Na+-H+ exchange - carrier removes excess H+ ions produced as a result of acid forming reactions in cells
         and maintains intracellular pH. System is regulated by pH - as pH falls, the activity of the exchanger
         increases
     Cl--HCO3- exchanger - HCO3- is ejected from the cell in exchange for Cl-. System is regulated by pH -
         its activity increases as pH rises (HCO3- is ejected when cytosol becomes too alcaline)
         Carrier proteins are asymmetrically distributed in most of the cells. In epithelial cells it contributes
to the transcellular transport of absorbed solutes (e.g. transport of glucose through intestinal epithelial cells
or resorption of Na+ in the proximal tubule of kidney).
         The combination of selective permeability and active transport across the plasma membrane creates
large differences in the ionic composition of the cytosol compared with the extracellular fluid. This enables
cell membranes to store potential energy in the form of ion gradients. These transmembrane ion gradients are
used to drive various transport processes, to convey electrical signals, to make ATP (in mitochondria).


                         ION AND WATER CHANNELS

        Ion channels are integral membrane proteins laying in the fluid lipid bilayer of the membrane. They
comprise aqueous pores, lined by polar groups and charged particles. More than 106 ions can pass through
such a single channel each second (100x more permeable than active transport). Direction of diffusion is
always along the electrochemical gradient.
Permeability of an ion channel is restricted by:

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   selective filter: the narrow part of the pore, has dimensions comparable to those of permeant ions  it
       can make the interactions needed for selecting among permeant ion
   channel gates: macromolecules with different conformation (open and closed, no continual change), the
       conformation changes in response to specific perturbation of the membrane:
1. Change of voltage across the membrane -         voltage-gated channels
2. Binding of a signaling molecule -               ligand-gated channels
     extracellular mediator (neurotransmitter) - transmitter-gated channel
     internal second messengers -                          nucleotide-gated channel
                                                           ion-gated channel
                                                           G-protein-gated channel
3. Mechanical stimulation -                         mechanically-gated channels

Approximately 50 types of ion channels have been described so far
  they are present in all animal and plant cells, probably evolved already at first eucaryotic cells
  in ontogeny Ca2+ and K+ channels appeared first (protozoa, algae)
  voltage gated Na+ channels emerged later (only after a nervous system evolved in multicellular animals -
      jellyfish, corals), voltage gated Na+ channels are designed for purpose of cell excitation (however, to
      this day, membrane potential changes must be "translated" into changes of cytoplasmic free-calcium
      concentration before they produce any output)

K+ leak channels (background, resting channels) are the most frequent channel in all animal cells
   permeable mainly to K+ (100 times more permeable to K+ than to Na+)
   they are responsible for maintaining the resting membrane potential
   single KCNKO channels switch between two long-lived states (one open and one closed) in a tenaciously
      regulated fashion. Activation can increase the open probability to approximately 1, and inhibition can
      reduce it to approximately 0.05. Gating is dictated by a 700-residue carboxy-terminal tail that controls
      the closed state dwell time but does not form a channel gate. The tail integrates simultaneous input
      from multiple regulatory pathways acting via protein kinases C, A, and G.

Voltage-gated Na+ channels
responsible for generating action potentials
two gates:        activation gate near the outside of the channel
                  inactivation gate - near the inside end
          When the membrane potential is near the resting level (-90 mV), the activation gate is closed,
preventing any entry of Na+. The inactivation gate is open.
          When the membrane potential becomes less negative than during the resting state (depolarized from
-90 mV toward -70 to -50 mV), a sudden conformation opens the activation gate - activated state. Na+ ions
pour inward (up to 20x106 ions/s), increasing permeability 500-5000 fold.
          Within next few 0.1 ms the inactivation gate automatically closes - inactivated state  channel has
remained opened for a few 0.1 ms. At this point the membrane potential begins to recover back toward the
resting membrane state. The activation gate may meanwhile close again.
          Inactivation gate will not reopen again until the membrane potential returns to the original resting
potential level  it is not possible for the sodium channel to open again, without the membrane is first
repolarized. This period is identical with the absolute refractory period of the plasma membrane.
Pharmacology of Na channels:
    tetrodoxin (TTX), present in tissues of some pufferfish and salamander; saxitoxin (STX), accumulated in
        tissues of filter-feeding shellfish; both have paralytic effect, make channels stay open too long,
        different binding site; also used for counting density of channels (35-500 Na channels per m2 of the
        plasma membrane)
    local anesthetics: block the passage through the pore, reach its receptor from cytoplasmic site

Voltage-gated K+ channel
   at the resting state, the gate is closed, K+ cannot leave the cell
   when depolarized, gate opens and allows K+ to flow outward
   gate closes comparatively "slowly"
   narrowest and most ion-selective channel
Function:
   1. to set resting potential
   2. to decrease the cell excitability
   3. to slow the rhythm of repetitive firing
   4. to repolarize from large depolarization
   5. to hyperpolarize

                                                         9
   6. to terminate periods of Ca2+ influx

Voltage-gated Ca2+ channel
    present in cell membranes and membranes of the sarcoplasmic reticulum
    opening is moderately fast, closing is comparatively very slow
    Ca2+ has a steep electrochemical gradient  the number of penetrating ions is very high
Transient rise of intracellular free Ca2+ results:
    1. cytoskeletal components interaction (muscle contraction)
    2. exocytosis or endocytosis (secretion, pino- and phagocytosis)
    3. protein phosphorylation
    4. modulation of the activity of other channels (K, Ca)
    5. inactivation of Ca channels
    6. increase of Ca2+ pumping
Electric current carried by Ca2+ depolarizes the cell membrane (theoretically up to 100mV), (in crustacean
    muscle it is sufficient to make action potential without any Na channels; similarly, in the dendritic
    membrane, spike potentials can be elicited)
If the density of Ca channels is high enough (hearth muscle), Ca2+ current extends the duration of the action
    potential
There are several classes of Ca channels, differing in their gating kinetics:
L type - cell membrane has to be depolarized strongly (more positive than -10 mV) to open the channel,
     inactivation occurs after several hundreds of milliseconds, high conductivity  well suited to a
     messenger function, permitting Ca2+ ions to enter the cytoplasm
T type - depolarization to only -70 to -60 mV suffice for initiate activation, channels will inactivate if the
     depolarization is maintained for ten to a few hundred milliseconds, low conductivity  suited to
     initiation of electrical activity and generating spikes.
N type - intermediate form
         Clinically useful "Ca antagonists" = blockers of Ca channels (e.g. used to block cardiac arrhythmias,
antihypertensive effects)
Na channels and Ca channels coexist in many excitable membranes (plateau in cardiac muscle)

Cl- channels
   rarely produce major permeability changes (with exception of some inhibitory synapses)

Transmitter-gated (ligand-gated) ion channel
  receptor is part of the channel
  ion selective, transmitter selective
  localized at specialized junctions (chemical synapses)
  they open transiently in response to the binding of a neurotransmitter
  convert extracellular chemical signals into electrical signals
  relatively insensitive to the membrane potential changes  they cannot by themselves produce a self-
      amplifying excitation  they produce graded changes of membrane potential, its magnitude
      depending on the amount of transmitter released

Acetylcholine driven transmitter-gated ion channel - ligand-gated channel
   densely packed at the neuromuscular junction (20,000 per 1m2) of skeletal muscle cell, similar are in
       CNS
   channel is a glycoprotein, composed of five transmembrane polypetides
   two acetylcholine receptors of the nicotine type are localized on the alpha chains
   transition changes are comparatively fast  transmission in neuromuscular junction is very fast
Function:
   1. when two acetylcholine molecules bind to the receptors, a conformation change is induced and the
       channel opens
   2. channel remains open for about 1 ms and then closes
   3. acetylcholine molecules dissociate from the receptor and are hydrolyzed by a specific enzyme
       (acetylcholinesterase)
   4. once freed from acetylcholine, channel reverts to its initial resting state
         Functionally similar are channels with receptors for gamma-amino-butyric acid (GABA) and
glycine, connected with Cl- channels

Ligand gated channels with an internal second messenger
Channels using G protein
                                                     10
         G proteins are intracellular peripheral membrane proteins coupling extracellular receptors to the
production of an intracellular response. They play a key role in mechanisms of cellular action of hormones
and transmitters, transduction of sensory stimuli, control of cell proliferation, regulation of ribosomal protein
synthesis. There are several different kinds of G proteins.
         G proteins are activated when GDP, bound to the alpha subunit, is replaced by GTP. GDP-DTP
exchange is catalyzed by a transient interaction of the external transmitter to the receptor. A single
transmitter molecule can activate many molecules of G protein  amplify the effect of the transmitter
1. activated subunit of G protein can directly gate an ion channel (muscarinically activated K+ channel in the
    heart
2. activated subunit can change activity of an enzyme producing a second messenger:
     a) adenylate cyclase - synthesis of cAMP
     b) phospholipase - formation of diacylglycerol (DAG) and inositol triphosphate (IP3)
3. second messenger affects the channel permeability:
     a) directly, when bound to the intracellular site of the ion channel
     b) by activation of a protein kinase that phosphorylates a channel and changes its functional state (more
         common than the direct ones)

Mechanically-gated channels (stretch-sensitive channels)
  sensitive to mechanical forces, they are present already in unicellular organisms, they operate in various
     types of mechanoreceptors (e.g. hair cells)
  the mechanical linkage between channel and membrane is provided by cytoskeletal string that pulls the
     gate and opens (closes) the gate when the membrane is stretched
  high number of strings attachments between the channel and the membrane allows force to be collected
     from a larger area of membrane
  location of the attachment to the membrane could be the basis for the directional sensitivity of certain
     mechanoreceptors
  mechanically gated channels discriminate poorly between Na+ and K+ ions

Aquaporins - water-channel proteins
         The plasma membranes of all mammalian cells are permeable to water, but to different extents. For
instance, the kidney proximal tubules are exceptionally water-permeable, whereas the ascending thin and
thick limbs of Henle’s loop, the distal convoluted tubule and the connecting tubule are known to be largely
impermeable to water. The highly water-permeable parts of the tubules have been shown to contain
membrane proteins - aquaporins.
         Aquaporine water-channel proteins are a family of membrane channels that serve as selective pores
through which water crosses the plasma membranes of many human tissues and cell types. Aquaporins are
freely permeated by water but not by ions or charged solutes. More than ten types of aquaporins have been
identified.
         The sites where aquaporins are expressed implicate these proteins in renal water reabsorption, CSF
secretion and reabsorption, generation of pulmonary secretions, aqueous humor secretion and reabsorption,
lacrimation, and multiple other physiologic processes.
         Activity of aquaporins can be controlled at different levels. They can respond with permeability
changes to the changes in the cell environment or to some signaling molecules. Also the density of active
aquaporins within the membrane can be controlled (ADH).


                MEMBRANE POTENTIALS

        Electrical potentials exist across the membrane of all cells of the body. They are employed in cell
"excitability":
1. In nerve cells, receptor cells and muscle cells membrane potentials are involved in acquiring, transmitting
   and integration of signals (acquiring and procession of information)
2. In glandular cells, macrophages, ciliated cells and muscle cells changes in membrane potentials control
   many of the cell's function:
     a) motility
     b) secretion
     c) synthesis
     d) proliferation, differentiation, tissue organization
Physical mechanisms of membrane potentials
Potassium movements

                                                      11
   potassium concentration is very high intracellularly, whereas outside it is very low
   the membrane in resting conditions is very permeable to the potassium ions but not to any other ions
   because of the large potassium concentration gradient, there is a strong tendency for K+ to diffuse
       outward.
   as they do so, they carry positive charges to the outside, thus creating a state of electropositivity outside
       the membrane and electronegativity on the inside, because of the negative anions that remains in the
       cell (large protein molecules)
   this new potential difference repels the positively charged potassium ions and prevents them from further
       diffusion to the exterior, despite still existing high potassium ion concentration gradient
   in mammalian nerve fiber, the potential difference required to prevent diffusion of K+ is about 90 mV,
       with negativity inside the cell - potassium diffusion potential

Sodium movements
   sodium concentration is higher extracellularly than inside the cells
   in the resting conditions permeability for sodium is low and the flow of Na+ represents only minor
      contribution to the membrane potential value
   when permeability for sodium increases, positive sodium ions diffuse along their concentration gradient
      inside the cell, carrying an inward positive current
   the membrane potential rises high enough to block further net diffusion of the sodium ions to the inside
   potential required to stop the diffusion of sodium ions (sodium diffusion potential) is about 61 millivolts
      with positivity inside the cell

Diffusion potential - Equilibrium potential
         The potential level across the membrane that will exactly prevent net diffusion of an ion in either
direction through the membrane (diffusion potential) is called Nernst Potential for that ion.
         The magnitude of this potential is determined by the ration of the ion concentrations on the both
sides of the membrane: the grater this ration, the greater the tendency for the ions to diffuse in one direction,
and therefore the greater is equilibrium potential.
                                           concentration inside
         EMF (millivolts) = ± 61 x log 
                                           concentration outside
         When a membrane is permeable to several different ions, the diffusion potential that develops
depends on:
   1. the permeability of the membrane (P) to each ion
   2. the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane
Goldman equation:
                                   CNaxPNa + CKxPK + CClxPCl
EMF (mV) = -61 x log 
                                   CNaxPNa + CKxPK + CClxPCl

Resting potential
        At the resting state almost only K+ leak channels are opened. As they are permeable practically
solely to K+, the potassium diffusion potential is the main component of the resting membrane potential.
(Because the plasma membrane is impermeable to sodium, its diffusion potential is very low, and therefore
contributes only a little to the resting potential.)
        Permeability of sodium and potassium channels undergoes very rapid changes during conduction of
the nerve impulse and it is primarily responsible for signal transmission in the nerve fibers.
        Everywhere, except adjacent to the surfaces of the cell membrane itself, the negative and positive
charges are exactly equal (for every positive ion there is a negative ion nearby). When positive ions are
pumped to the outside of the membrane, these positive charges line up along the outside side, and on the
inside the anions left behind line up. This creates a dipole layer between the outside and inside of the
membrane - the cell membrane functions as an electrical capacitor.
     an incredibly small number of ions needs to be transferred through the membrane to establish the
       resting potential (only about 1/10 000 000 of the total positive ions inside)
     equally small number of positive ions moving from outside to the inside can reverse the potential from
       -90 mV to +35 mV.


MEMBRANE POTENTIALS CHANGES AND THEIR PROPAGATION

        In several kinds of cells, changes of membrane potential serve to the information processing and
transmission. The electrical messages of excitable cells are changes of the electrical potential difference

                                                      12
across the cell surface membrane. By convention, a cell is said to depolarize if the membrane potential
becomes more positive, to repolarize when it returns toward the original negative value, and to hyperpolarize
if the membrane potential goes more negative than the resting value.
         For the most rapid transmission over long distances (along the axons or along the length of muscle
fibers), action potential (action potential, spike) has evolved. In contrast, slow potentials do not propagate
at constant amplitude. They are responses of highly localized transducing mechanisms, graded in amplitude
and duration in accordance with the amplitude and duration of the stimulus being transduced. Slow
potentials have no threshold. They arise at chemical synapses in response to the chemical transmitter and at
sensory receptors in response to their appropriate stimuli. They sum spatially and temporally with other slow
potentials in the same cell. Some slow potentials are depolarizing, and others are hyperpolarizing.
Membranes of those cells which do not generate actions potentials (glandular cells, macrophages, ciliated
cells and others) also respond with slow potential changes to their adequate stimuli. Slow membrane
potential changes are responsible for the specific activity of cells (motility, secretion, synthesis, proliferation,
differentiation, tissue organization). Activity of voltage gated Ca2+ channels and calcium flow can be
involved as a triggering mechanism.

Passive electrical properties of membrane
         Cell membranes are very good insulators - high electrical resistance (Ohm/cm2), high electrical
capacitance.
         The axial resistance (Ohm/cm) depends on the diameter of the process (axon or dendrite).
         The current that is injected flows out across the membrane by several pathways along the length of
the process. Each of these pathways is made up of two resistive components in series: a total axial resistance
and a membrane component. More current flows across the membrane near the site of injection (lower
resistance because of smaller axial resistance). The decay with distance has an exponential shape. The
length constant is the distance along the dendrite to the site where the membrane potential has decayed to
1/e, or 37% of its value at x=0. The better the insulation of the membrane (the higher is the membrane
resistancy) and the better the conducting properties of the inner core (the lower is the axial resistancy), the
grater is the length constant and the further is current able to spread efficiently along the process. Typical
length constant values fall in the range of 0.1-1.0 mm.
         The passive spread of voltage changes along the neuronal membrane is called electrotonic
conduction - an essential condition of the spatial summation.

Active electrical properties of membrane
        Action potential is a sequence of events, resulting from the operation of ion channels in the neuronal
membrane. Only membranes equipped with sufficient density of voltage gated channels are able to
generate and propagate an action potential - "excitable" membranes.
1. Resting stage (before the action potential occurs) - membrane is polarized mainly because of the
   conductance for potassium ions is much higher as that for sodium (only the leak channels are opened)
   (diffusion potential of the potassium contributes most to the total value of the membrane potential, about
   -90 mV in neuronal fibers, -40 to -60 mV in small neurons)
2. Depolarization stage - when membrane becomes depolarized either from external sources (artificial
   stimulation) or from internal sources (influence of the neighboring membrane) voltage-gated Na+
   channels open, and conductance for sodium increases up to 5000 times. Sodium diffusion potential
   becomes the largest component of the total membrane potential (sodium potential subtracts from the
   potassium diffusion potential). Membrane potential drops from about -90 mV to +10 mV.
3. Repolarization stage - within few 1/10 ms the gate of voltage gated potassium channels opens, bringing
   some more K+ outside the membrane (increasing significance of the potassium diffusion potential). At the
   same time inactivation gate of Na voltage-gated channels close (decreasing significance of the sodium
   diffusion potential). Membrane potential returns to its baseline level.
4. "Positive" afterpotential (overshoot) - additional increase of the membrane potential
   (hyperpolarization) sometimes occurs for several ms after the membrane potential reached its baseline
   level (called positive, because formally membrane potentials were recorded extracellularly, where this
   event is positive). The positive afterpotential results from still opened voltage-gated potassium channels,
   when sodium channels were already closed (inactivated).

Role of other ions during the action potential
        The impermeant negatively charged ions inside the cell (proteins, phosphates, sulphates) cannot
leave the interior of the cell. Any deficit of positive ions leaves an excess of the impermeant anions 
impermeant anions are responsible for negative charge inside the membrane when there is a deficit of
positively charged ions (K+)
        Calcium ions became important in membranes with high density of Ca2+ voltage-gated channels
(nerve terminals, some dendrites, membrane of striated muscles, cardiac muscle, smooth muscle, secretory

                                                        13
cells). Because of their high diffusion potential, they can contribute to the amplitude of action potential,
because of their slow activation and inactivation they contribute to the duration of action potential or to the
level of the resting potential (long-term depolarization). In some dendrites and non-nervous cells without
voltage-gated Na channels, the action potential is caused almost entirely by activation of calcium channels.
         Calcium ions are also important for the voltage level at which the sodium channels became activated
(threshold level). When there is a deficit of calcium ions, the sodium channels are activated by a smaller
depolarization (5-10 mV instead of 15-30 mV). The nerve fibers become highly excitable and spontaneous
discharges occur in peripheral nerves, often causing muscle "tetany" (lethal when it reaches the respiratory
muscles).
         During the resting stage of membrane potential, chloride ions are repelled from the inward diffusion
because of the direction of the membrane potential. During the action potential, small quantities of chloride
ions diffuse into the nerve fibers because of the temporal loss of the internal negativity. These movements
are not large enough to alter the fundamental process.

Initiation of the action potential
         As long as the membrane of a nerve fiber remains undisturbed, no action potential occurs. If any
event causes enough initial depolarization, the rising voltage itself will cause many voltage-gated channels to
open. The rapid depolarization, which results, causes opening still more voltage-gated channels and
subsequent deeper depolarization (or transpolarization) - example of a positive-feedback mechanism.
Depolarization from -90 mV to about -65 mV (15-30 mV) will usually cause an action potential in a nerve
fiber (threshold level).
         If the membrane potential rises very slowly (over many milliseconds), the inactivation gates will
have time to close at the same time that the activation gates are opening  slow depolarization of a nerve
fiber either requires a higher threshold voltage than normal, or prevents firing entirely (accommodation of
the membrane to the stimulus).

Refractory period
        A new action potential cannot occur in an excitable fiber as long the membrane is still depolarized
from the preceding action potential
        The cause of this is that shortly after the action potential is initiated, the sodium channels (or Ca
channels) became inactivated, and any amount of excitatory signal will not open the inactivation gates -
absolute refractory period. For large myelinated fibers it is about 2 ms.
        Following the absolute refractory period is a relative refractory period, lasting about one quarter to
one half as long as the absolute refractory period. During this time, stronger than normal stimuli can excite
the membrane because:
   a) some sodium channels are still inactivated
   b) potassium channels are still opened - membrane is hyperpolarized

Propagation of the action potential
         Action potential elicited at any one point on an axonal membrane, excites adjacent portions of the
membrane, resulting in propagation of the action potential
 1. depolarization of the axonal membrane (potential reversal from -90 mV to +10 mV) elicits "local
     circuits" current flow between the depolarized areas and adjacent resting membrane areas. Electrical
     charges carried by the inward diffusing sodium ions flow inward through the depolarized membrane and
     then for several millimeters along the core of the axon.
 2. These positive charges can depolarize the axonal membrane in a distance up to several millimeters.
 3. If the depolarization in the neighboring portion of axon reaches the threshold level, voltage-gated Na
     channels activate, causing progressively more and more depolarization.
 4. The newly depolarized area becomes again a source of new "local circuit" flow.
         Axonal membrane has no single direction of propagation. Action potential can travel in both
directions away from the stimulus. However, anatomical organization of neuronal pathways usually assures a
unidirectional propagation only.
         If a stimulus elicits an action potential at a normal fiber, depolarization process will travel over
entire membrane. On the other hand, if the stimulus fails to elicit sufficient depolarization, no action
potential arise (all or nothing principle).
Most of the action potential propagates on the basis of voltage-gated Na channels:
         axons of all animals
         striated muscles
         cardiac atrial and ventricular muscle (initial depolarization phase)
         cardiac Purkyně fibers
         dendrites of central neurons
Some membranes employ voltage-gated Ca channels:

                                                     14
        nearly all invertebrate muscle
        cardiac sinoatrial and atrioventricular nodes
        vertebrate smooth muscle
        dendrites of central neurons

Propagation of the action potential along myelinated fibers
         During the propagation of an action potential along the myelinated nerve, ions forming "local
circuits" cannot flow through the thick myelin sheath, but they can flow through nodes of Ranvier. In this
part of the axonal membrane we find a high density of voltage-gated Na channels. Action potential can occur
only at the nodes and therefore it propagates from node to node - saltatory conduction. It increases the speed
of propagation 5-50 fold and decreases the energy requirements.

Re-establishing sodium and potassium ionic gradients
        Transmission of each impulse along the nerve fiber reduces infinitesimally the concentration
difference of sodium and potassium. Usually several tens of millions of action potential can be transmitted
before the concentration difference run down to the point that action potential conduction ceases.
        To avoid changes of ion concentration differences, the Na+K+pump operates continuously to
"recharge" the nerve fiber. The whole process requires energy (ATP) and produces heat.

Plateau in some action potentials
         In some membranes the depolarization during an action potential is not followed by a rapid
repolarization. Instead potential remains for some period of time on a plateau near the peak of the action
potential (e.g. in heart muscle fibers).
         First part of such action potential results from an action of voltage-gated Na channels. Plateau is
caused by a second set of voltage-gated channels, the Ca channels, which open with a certain delay and
remain opened for even several tens of second. At the same time, the voltage-gated K channels are activated
with a long latency, opening at the same time that the slow Ca channels begin to close.

Rhythmicity of certain excitable tissues
         Repetitive self-induced discharges (rhythmicity) occur normally in the heart, in most smooth muscle
and in many of the neurons of the CNS. Membranes capable to generate rhythmically action potentials are,
in their natural (resting) state more permeable for sodium and/or calcium ions. The inward flow of these ions
depolarizes the membrane to the threshold level of voltage-gated Na+ (or Ca2+) channels and therefore elicits
the action potential Repolarization is usually followed by a period of an increased permeability to potassium
and therefore by a period of hyperpolarization. It delays the onset of the new depolarization period.


                      CELL COMMUNICATION AND SIGNAL PROCESSING

         Unicellular organisms were present on earth 3.5 milliards years ago. First multicellular organisms
appeared about 1 milliard years ago  it took 2.5 milliards years to elaborate mechanisms that enable cells
to communicate with one another so as to coordinate their behavior. Intercellular signals, interpreted by
complex machinery in the responding cell, allow each cell to determine its position and specialized role in
the body.
Cells in a multicellular organism need to communicate with one another in order to:
  1. to control their growth and division
  2. regulate their development, differentiation, and organization into tissues
  3. to coordinate their functions
Within the multicellular organism the information is transmitted by means of:
 1. products and intermediate products of metabolism
 2. specific signaling molecules
 3. ion and electrical gradients and their changes

Output signal transmission:
Signaling molecules: proteins, small peptides, amino acids, nucleotides, steroids, retinoids, fatty acid
derivates, dissolved gasses (nitric oxide, carbon monoxide).
   a) cells secrete chemicals that transmit information to cells some distance away (humoral transmission of
       an information) - exocytosis, detachment of membrane-bound signaling molecules
   b) cells display plasma membrane-bound signaling molecules that influence other cells in direct contact
       (important during organization of the tissue [development] and in immune responses)


                                                        15
   c) cells form gap junctions that directly join the cytoplasm of the interacting cells, allowing exchange of
      small molecules

Signal recognition and processing:
          The target cell responds to the given signal by means of a specific protein called a receptor. It
specifically binds the signaling molecule and then initiates a response in the target cell.
  a) cell surface receptors (transmembrane proteins) are designed to bind an extracellular signalling
      molecule (secreted or membrane bound)
  b) intracellular receptors - signaling molecule (small and hydrophobic) has to enter the cell to activate it
          Any given cell in a multicellular organism is exposed to many of different signals from its
environment (soluble, membrane bound, bound to extracellular matrix). Each cell is therefore programmed
to respond to a specific combination of signaling molecules. One set of signals may trigger an increased
activity, another differentiation or proliferation. Most cells are programmed to depend on a specific set of
signals for survival: when deprived, a cell will activate the program for apoptosis (programmed cell death).
The specific way a cell reacts to its environment varies according to:
    the set of receptor proteins that cell possesses through which it is tuned to detect a particular subset of the
       available signals
    the intracellular machinery by which the cell integrates and interprets the information that it receives
 different cells can respond differently to the same chemical signal
(E.g. acetylcholine effects in skeletal muscle cell, heart muscle cell, secretory cell; alpha and beta adrenergic
receptors.)

Intercellular signaling mechanisms vary in the distance over which they operate:
 a) Paracrine signaling - cells secrete local chemical mediators, which are active only on cells in the
      immediate environment. They are distributed by diffusion in the interstitial fluid and they are rapidly
      inactivated.
 b) Endocrine signaling - specialized endocrine cells secrete hormones, which travel through the blood
      stream to influence target cells distributed widely throughout the body.
 c) Synaptic signaling - cells of nervous system secrete neurotransmitters at specialized junctions called
      chemical synapses, the neurotransmitter diffuses across the synaptic cleft (about 50 nm), and acts on
      adjacent postsynaptic target cell
 d) Autocrine signaling - transmission of a molecular signal released into the intercellular fluid back to the
      cell of origin or to neighboring identical cells.
In each case the target cell responses to a particular signal by means of specific proteins - receptors that bind
    the signaling molecule and initiate the response.

Endocrine cells are usually organized in discrete glands. Signaling molecules are secreted into interstitial
fluid and:
        diffuse into capillaries
        enter the blood stream
        escape from capillaries in to the interstitial fluid
        bind to the receptors of their target cells
The whole process
    is relatively slow (diffusion and transport takes minutes, developing of response may take up to several
        days)
    specificity of signaling depends on the chemical properties of the signal and the receptor (a single
        signaling molecule often has different effect in different target cells [acetylcholin - contraction of
        skeletal muscle + decrease of force of contraction of heart muscle]  respond is based on different
        target receptor proteins or different internal machinery to which receptors are coupled)
    signal molecules are greatly diluted and must be able to act at very low concentrations
    some cellular responses to chemical signals are rapid and transient (insulin and fat or muscle cells),
        others are slow and long lasting (developmental changes induced by sexual hormones)
Nerve cells - transmit signals over long distances by means of electrochemical impulses (up to 100 m/sec)
    specificity of action is given by anatomical relations between the nerve cells (and target cells)
    their chemical signals act in either paracrine or the synaptic mode
    neurotransmitters are much less diluted - the amount released is much smaller

Processing of chemical signals
1. The signal molecule must be recognized by a specific cell receptor
2. The signal molecule-receptor complex must be coupled to a signal-generating mechanism


                                                       16
3. The generated signal (second messenger) then causes positive or negative quantitative changes in the
  intracellular processes by altering the activity or concentration of enzymes, carrier proteins, transcription
  factors, etc.
Only lipid-soluble signaling molecules can enter cells directly. Water-soluble molecules are too hydrophilic
    to pass directly through the lipid bilayer of the target cell plasma membrane  they have to bind to
    specific receptors on the cell surface.
Most water-soluble signaling molecules are inactivated within minutes of entering the blood, local chemical
    mediators and neurotransmitters are removed from the extracellular space within seconds or
    milliseconds (biological half-time). Lipid-soluble signaling molecules (transported in the bloodstream
    by binding to specific carrier protein) persist in blood hours (steroid hormones) or days (thyroid
    hormone).
Many locally acting signaling molecules are released by cells that are specialized for this purpose. Other
    types have more widespread origin. (Prostaglandins, 20-carbon fatty acid derivatives, are made by cells
    in all mammalian tissues. They are cleaved from membrane phospholipids and continuously released to
    the cell environment. When cells are activated by some chemical signals, the rate or prostaglandin
    synthesis is increased  the local increase of prostaglandins influences by autocrine stimulation
    mechanism for amplifying and/or prolonging a response to the initial stimulus.)

Cell-surface receptor systems
Receptors of water-soluble signaling molecules (e.g., neurotransmitters, protein hormones, protein growth
    factors, catecholamines) are large complexes, often composed of subunits, they appear to be
    glycoproteins with their structure resembling that of immunoglobulins.
A specific extracellular portion of the receptor binds the signaling molecule. This part of the receptor may be
    an internal image of a complementary amino acid sequence within the signaling molecule.
After receptor activation is completed, internalization of the complexes occurs (endocytosis, sometimes via
    coated pits).
Within the cell, lysosomal degradation of the complex occurs, with either destruction of the signaling and
    receptor molecules or recycling of the receptor molecules back into the plasma membrane.
Most cell-surface receptor proteins belong to one of three classes:
 1. Ion-channel-linked receptors (=transmitter-gated ion channels) are involved in rapid signaling
    between electrically excitable cells and/or may mediate intracellular changes of Ca2+.
 2. G-protein-linked receptors act indirectly to regulate the activity of a separate plasma-membrane-
    bound target protein (enzyme, ion channel). The interaction between the receptor and the target protein
    is mediated by a third protein, called a trimeric GTP-binding regulatory protein (G protein). The
    activation of the target protein either alters the ion permeability of the plasma membrane (ion channel)
    or it alters the concentration of one or more intracellular mediators (enzyme) (which act in turn to alter
    the behavior of yet another proteins in the cell).
 3. Enzyme-linked receptors either function directly as enzymes or are associated with enzymes. Usually
    they have their ligand-binding site outside the cell and their catalytic site inside. The great majority of
    these enzymes are protein kinases that phosphorylate specific sets of proteins in the target cell.

Second messengers
G-proteins couple signaling molecule-receptor complexes to different effector systems:
 a) In the adenylyl cyclase-cAMP system, the plasma membrane enzyme adenylyl cyclase catalyzes
    formation of cAMP from ATP with Mg++ as cofactor. Stimulatory G-proteins increase intracellular
    cAMP levels, inhibitory G-proteins decrease intracellular cAMP levels. The actions of cAMP are
    terminated by its hydrolysis, modulated also via a G-protein. An increase in cAMP brings about:
       activation of protein kinase A, which, in turn, activates a number of enzymes in numerous metabolic
           pathways by phosphorylating their kinases
       stimulation of phosphorylation which may deactivate some other enzymes - it results in a cascade of
           effects that change the flux of metabolites in the cell (storage or release of metabolites)
       alteration of the gene expression - it results in stimulation or inhibition of RNA polymerase and
           ultimately stimulates or inhibits synthesis of a specific proteins
 b) As a result of signaling molecule occupancy of its receptor, a specific G-protein activates channels in
    the plasma membrane through which extracellular calcium ions can enter the cytoplasm. Ca2+ may also
    be mobilized from intracellular reservoirs (endoplasmic reticulum, mitochondria). Calcium combines
    with a specific binding protein, calmodulin. Calcium-calmodulin complexes amplify or diminish the
    activities of a variety of enzymes.
 c) Action of G-proteins is mediated by plasma membrane phospholipids. G-protein activates the
    membrane-bound phospholipase-C, which ultimately results in formation of diacylglycerol and inositol-


                                                     17
    1,4,5-trisphosphate (IP3). The diacylglycerols are potent activators of protein-kinase C. IP3 triggers
    mobilization of calcium from its intracellular stores  amplification of protein-kinase C activity.
        Other second messengers employed in signaling molecule interaction with plasma membrane
receptors have been described (e.g., cGMP, atrial natriuretic hormone). A single type of signaling molecule
may operate through one or more of second messengers simultaneously or in sequence. Each messenger may
subserve a different function of a signaling molecule.

Signaling mediated by intracellular receptors
1. Nitric oxide gas (NO) signals by binding directly to an enzyme inside the target cell. NO is produced as a
   local mediator by various cells (blood vessel endothelial cells activated by acetylcholine, activated
   macrophages and neutrophiles). NO is made by the enzyme NO synthase by the deamination of amino
   acid arginine. It diffuses easily and acts locally because it has a short half-life (5 to 10 sec). In target cells
   NO reacts with iron in the active site of the enzyme guanylyl cyclase, stimulating it to produce cGMP
   (cyclic Guanosin Mono Phosphate). Carbon monoxide (CO) acts in the same way as NO, by stimulating
   guanylyl cyclase.
2. Steroid and thyroid hormones, retinoids, and vitamin D (small hydrophobic molecules) enter the cell and
   bind to intracellular receptor proteins. Binding of the signaling molecule transforms or activates the
   receptor (conformation change) and through several interactions DNA molecule is activated and
   transcription initiated. Translation of the RNA message in the cytoplasm results in synthesis of specific
   target proteins of the signaling molecule. In some cases, suppression of gene transcription can also result
   (e.g., steroid or thyroid hormone effects). Proteins whose synthesis is regulated up or down by the
   particular signaling molecule may be enzymes, structural proteins, transcriptional proteins, or proteins
   that are exported by the cell. Hours are usually required for many of their biological effects to be evident.
   Some of the primary-response proteins turn on secondary-response genes thus triggering the delayed or
   sustained response. Retinoids (e.g., retinoic acid) are made from vitamin A and they play important roles
   as local mediators in vertebrate development.

Role of calcium in the information transmission
         Already in the early phylogeny, calcium became one of the most universal signals, which control
variety of cellular processes.
At the cellular level, Ca2+ is derived from two sources:
   It can enter from outside the cell by passing through channels within the plasma membrane.
   It can be released from internal Ca2+ stores through channels in the endoplasmic or sarcoplasmic
       reticulum.
   In excitable cells, the major pathway for Ca2+ influx is via highly Ca2+-selective voltage-gated Ca2+
channels. In skeletal muscle cells, an additional voltage-sensitive pathway is provided that release Ca2+
from the sarco- and endoplasmic reticulum. Voltage-independent Ca2+-permeable channels comprise the
most numerous and varied Ca2+-influx pathways in cells. Many ligand-gated ionotropic channels are
relatively non-selective for cations and can pass substantial amounts of Ca2+. Other voltage-independent
channels respond to sensory stimuli. Hair cells of the ear have mechanically opened Ca2+-permeant
channels. Light, odorants and taste molecules operate through a signal cascade that is regulated by the
cyclic nucletotides cAMP or cGMP.
         When Ca2+ channel opens, a highly concentrated plume of Ca2+ forms at the intracellular mouth of
the channel and dissipates rapidly by diffusion. Such localized signals, which can originate from channels in
the plasma membrane or on the internal stores, represents the elementary events which control activity of
individual intracellular organelles or sets of organelles. The spatio-temporal summation of these elementary
events brings about global responses.
Elementary events generate localized increase of Ca2+ concentration that can activate individual
   intracellular organelles:
       export of intracellular material (exocytosis)
       import of macromolecules or particles (endocytosis)
       membrane excitability
       synaptic plasticity
       metabolism of mitochondria
       growth-cone migration
       mitosis
Intracellular global waves of Ca2+ concentration increase are produced by coordinating activity of
   elementary events and spread throughout the cell. They can affect the general orientation of cell activity:
       skeletal muscle contraction
       smooth muscle contraction
       cardiac muscle contraction
       liver metabolism

                                                        18
      gene transcription
      cell proliferation
      apoptosis
Intercellular global waves spread to neighboring cells within a tissue and coordinate their activity:
      contraction waves in the smooth muscle tissue (e.g. bile flow)
      cilliary beating
      glial cell function
      wound healing
      insulin secretion


                         SENSORY TRANSDUCTION

General properties of sensory transduction systems
Sensory input is the origin of all we know.
Although all living cells have the ability to translate physical events into biological signals, some cells
    specialized to provide the nervous system with information about the events in external and internal
    environment - sensory receptors.
Sensory receptors receive physical stimuli and transduce (convert) them into biological signals.
Input to sensory receptors:        mechanical - mechanoreceptors
                                   electromagnetic - photoreceptors
                                   chemical - chemoreceptors
                                   thermal - thermoreceptors
                                   (electrical - electroreceptors)
To detect physical stimuli, sensory receptor cells are equipped with specific set of membrane proteins,
    receptor proteins or sensors acting as "receptor cell's receptor".
Integration of the physical stimuli with the sensor triggers a structural rearrangement (conformation), which
    eventually results in a change in the ionic permeability. There is a great variety of sensor-related channel
    interactions: from the direct influence to the effects of internal messengers.
Output signal of a sensory receptor is a change in membrane potential. The membrane permeability change
    (decrease or increase) release energy stored in the form of ion concentration gradients  it can produce
    and amplified signal.
The linkage between the stimulus-induced conformational change of the sensor and the change of the ionic
    permeability of the receptor cell membrane is called transduction process. To increase the efficiency of
    the transduction process, sensors and related ion channels are concentrated in a small, distinct region of
    the cell - transduction site.
Efficiency of individual stimulus sensitive channels also requires that they operate as much as possible in
    unison, the more synchronously individual channels behave, the more their separate contributions are
    able to sum. In many sensory receptors synchronization is aided by accessory structures. They act as an
    interface between the external environment and the sensory receptor. They can focus, filter or modify the
    appropriate stimuli.
The accessory structures can be part of the receptor cell (hair in hair cells) or completely separate elements,
    that are either simple (e.g. mucous covering of taste receptors), or very elaborate (e.g. mechanical linkage
    that couples sound pressure to stimulation of the hair cell receptors). Accessory structures can also
    protect the delicate transduction site of the receptor from inappropriate stimuli or from stimuli of an
    extensive strength.
The tiny voltage changes produced by individual stimulus-sensitive channels sum together and produce a
    larger change in membrane potential - receptor potential.
Receptor potential is a local potential change, amplitude of which depends on the intensity of stimulus (from
    few mV up to 100 mV). Direction of the membrane potential (depolarization or hyperpolarization)
    change depends on the kind of channels opened and the ion concentration gradients across the membrane.
In most of receptors, the growth of the response with increasing stimulus intensity may be approximated by
an equation:
                  sensation intensity = constant x logarithm of the stimulus intensity
     Receptors are most sensitive to the weak stimuli and less sensitive to the stronger ones.
Maximum response is limited by the operation properties of the transduction response. Stimulus that evokes
    a maximum response is a saturating stimulus.
          When a continuous stimulus is applied, the receptor responds at a high impulse rate at first, then at a
progressively lower rate until finally many of them no longer respond at all - adaptation of receptors. The
speed of adaptation differs in different sensory systems as well as in different receptors of the same systém:
 a) elements with high adaptation - signal changes detection - information can be used for prediction of the
     subsequent movement and to an adjustment to it (neck reflexes)
                                                      19
 b) elements with low adaptation - information about the intensity of a signal (aortal and carotid
     baroreceptors, muscle spindles)
The release of transmitter as a result of the receptor potential occurs at the opposite end of the cell from the
   transduction site. In some cells, the receptor potential directly modulates transmitter release (an increase
   with depolarization of the membrane, and decrease with hyperpolarization). In some receptor cells the
   transducing area and synaptic terminal are separated by a long distance of a neuronal fiber. The receptor
   potential (here called a generator potential) triggers one or more action potentials that are conducted to
   the synaptic terminal, where they provide signal for the release of specific amounts of transmitter.

Mechanoreceptors
        Cells that transduce mechanical stimuli into bioelectric signals are the most common type of sensory
receptors (receptors in skin, muscles, tendons and ligaments, joints, fascias, blood vessels, bladder, cardiac
muscle, inner ear). Accessory structures may be very simple (receptors of touch) or very complex (peripheral
auditory system).

         Receptive part of a Pacinian corpuscle is formed by an unmyelinated nerve terminal, within an
onion-like capsule (an accessory structure). Transduction region represent the first nodes of Ranvier into of
the myelinated nerve fiber.
   brief mechanical stimulus presented to the receptor capsule results a depolarization of the inner neuronal
       membrane - depolarizing receptor potential
   if the amplitude of the receptor potential is large enough it spreads to the first nodes of Ranvier and here
       elicits action potentials (by opening the voltage-gated Na channels)
   Pacinian corpuscle has a high adaptation rate, it is sensitive only to transient changes that occur when the
       stimulus is turned on or off. It has a certain level of directional sensitivity.
         Hair cells are responsible for detection of sound, linear and angular acceleration and gravity (water
motion in fish). This wide range of sensitivities is due to differences in the design of their sensory structures.
Together with supporting cells they separate two dissimilar solutions. The basolateral surface is bathed in
normal interstitial fluid, the apical membrane gives rise to a bundle of hair-like projections (stereocilia +
kinocilium) which are bathed in a high-potassium, low calcium solution. Attached to cilia are mechanically-
gated channels.
   when the cell is in the resting state, a few nonselective cation channels in the apical membrane are open;
       since potassium is the predominant cation in the endolymph, it enters the cell along its electrical
       gradient (interior of the cell is negative) and causes a steady inward current
   deflection of the cilia pull directly on the channel and cause it open or close (moving the hair bundle
       toward the kinocilium opens more channels, the inward receptor current increases and the cell
       depolarizes; moving bundle in the opposite direction closes channels causing hyperpolarization
   the difference in the potassium concentration of endolymph and extracellular fluid is maintained by the
       supporting cells

Photoreceptors
          Photoreceptors are designed to interact and convert the energy of the electromagnetic rays in the
visible light band. Photoreceptors in the human retina:
cone cells (cones) serve for color vision and perception of fine details, and they require bright light
rod cells (rods) provide for monochromatic vision in dim light
    Photoreceptor cell can be morphologically divided into three parts: outer segment, inner segment and
        synaptic terminal. They have probably evolved from epithelial cells and their outer segment is
        therefore separated from the inner one by a modified cilium. The outer segment is the transduction
        site. In cones it is formed by a highly infolded surface membrane, in rods it is filled with sac-like
        disks.
    Membrane of disks contains photosensitive rhodopsin molecules. Each rhodopsin molecule consists of a
        transmembrane glycoprotein (opsin) with a prosthetic group - chromophore (11-cis-retinal).
    In the dark, the photoreceptor is strongly depolarized due to open Na channels in the plasma membrane of
        the outer segment. The depolarization (approximately -40 mV in darkness) causes a K+ ion current
        ("dark current") to flow through inner segment K+ channels and holds voltage-gated Ca channels open
        in a synaptic region. The resulting influx of Ca2+ produces a steady release of neurotransmitter.
    Absorption of a photon turns 11-cis-retinal to all-trans-retinal. It makes the opsin protein to conform. Via
        a G protein (transductin) it activates cyclic-GMP phosphodiesterase which rapidly hydrolyze cGMP
        (reduces its level). cGMP keeps the Na channels open  the fall of cGMP closes Na+ channels.
    Illumination thus causes the Na channels to close, so that the receptor potential takes form of a
        hyperpolarization, which leads to a decrease of Ca2+ influx and consequently a decrease in the rate of
        transmitter release.


                                                       20
   Because the transmitter acts to inhibit many of the postsynaptic neurons, illumination frees these neurons
       from inhibition - results in an excitation.
   The suppression of dark current and the amplitude of the hyperpolarizing receptor potential are graded
       according to the number of absorbed photons.
   After a delay (about one minute) all-trans-retinal dissociates from the opsin by hydrolysis and is released
       to the cytosol. There it reverts to the 11-cis-form, which then reassociates with opsin and is
       reembedded into the membrane.
   In cones three classes of photopigment were found. They all have the same chromophore (11-cis-retinal)
       with different membrane proteins (opsins). It determines the differences in the absorption spectrum in
       each class of photopigment. The transduction process is basically the same as in rods.

Chemoreceptors
         All living cells are able to respond selectively to specific chemicals in the local environment. The
presence of such chemical is monitored by specific receptor proteins (sensors) on the cell surface. Each type
of sensor has a high affinity for a particular compound, but few are specific for a single compound.
Chemoreceptors provide information about the composition of the food (taste), air (olphaction),
concentration of O2, CO2, and other substances in body fluids.
   interaction of a certain chemical with appropriate receptor of a ligand-gated channels triggers a sequence
       of events (usually via an internal massager) resulting in opening of closing of these channels
   the amplitude of the resulting receptor potential is graded with the concentration (number of activated
       receptors)
   beside an amplifying effect, the use of second messenger provide a mechanism for separating the site of
       receptor - ligand binding from the site of the ionic permeability change (it would ensure that the
       receptor potential is not affected by local changes in ionic concentrations)

Thermoreceptors
        Distant thermoreceptors (rattlesnake infrared detector) - axon terminals filled with mitochondria.
Transduction is based on changes of molecular vibrations (infrared light has very low energy - strong
amplification process is necessary). Similar organization is expected in cutaneous and central
thermoreceptors.

Electroreceptors
         Voltage sensitive ion channels (Na+ channel, Ca2+ channel) are specialized sensors that monitor
electric field. They can detect changes of the membrane potential, but some specialized group of these
sensors organized in electroreceptors, can detect extracellular electric fields (in certain species of fish they
play a role in navigation, location of prey and predators).
         In some organisms receptors for magnetic fields changes were found (pigeon, honey bee) -
importance for navigation.


                         THE CYTOSKELETON

Cytoskeletal proteins are present in all eucaryotic cells (absent in procaryotic cells). Emergence of
cytoskeleton appears to be a crucial factor of evolution.
Function of the cytoskeleton:
 1. determining the shape and polarity of the cell
 2. ability to withstand external forces
 3. attachment of cell organelles (or components of organelles)
 4. cell movements (cytomusculature)
       a) active changes of the cell shape
       b) cell locomotion
       c) muscle contraction
       d) active movement of organelles
       e) cell division, development, and growth
       f) cell migration
 5. interaction with neighboring cells (through intercellular junctions or by the effect on extracellular
    matrix)
       a) in the process of the tissue organization
       b) in coordinated functions
Ad 1 and 2 - Cytoskeleton plays the preeminent role in the determining the shape and polarity of the cell.
  The cytoplasm contains a complex three-dimensional network of protein filaments.

                                                      21
   Cortex (membrane skeleton, subplasmalemal skeleton) - mainly a meshwork of crosslinked action
      filaments
   Some components of the cytoskeleton are bound to transmembrane proteins (peripheral membrane
      proteins) by noncovalent interactions
      Spectrin - peripheral protein of the cytoplasmic side, the principal component of the cytoskeleton, one
      of the contractile proteins, enables cells to withstand the stress on its membrane (e.g., in erythrocytes
      as they are forced through narrow capillaries)
      Ankyrin - responsible for binding the spectrin cytoskeleton to the plasma membrane, similar protein
      can anchor proteins of ion channels in certain domains of the plasma membrane
   In some cells, cytoskeleton determines formation and function of specialized membrane structures:
      flagelli, cilia, microvilli, stereocilia, kinocilia. (Stereocilia are very large, specialized microvilli. They
      are formed as plasma membrane protrusions and contain a bundle of actin filaments in their core).
Ads 3 - Membrane-bounded organelles are linked to the cytoskeleton. Their mutual position as well as all the
  position changes is determined by cytoskeleton. Also the structure of the cytoplasm itself is very
  complex. Spaces between cytoskeletal components are filled with granular "ground substance". Even
  soluble enzymes (e.g., those involved in glycolysis) are bound to specific sites on myofibrils or on
  cytoskeletal fibers in other cells. Enzymes in the cytosol are thus physically clustered, pathway by
  pathway, and attachment to the cytoskeleton permits a more efficient channeling of intermediates within
  each pathway.
Ad 4 - During cell division, chromozomes and other organelles are attached to specially arranged
  cytoskeletal fibers and pulled to the opposite poles of the dividing cell. Membrane skeleton then finishes
  the division into two daughter cells.
  When a cell migrates, microtubules and the actin-based cytoskeleton acts in concert. In the migrating
     cells, polarity is generated (leading and trailing end).
  For nerve cells development, growth cones are the characteristic components. They contain both
     microtubules and actin filaments. Each axon and dendrite is pulled out of the body under tension
     generated by the growth cone at the growing tip of the process.
Ad 5 - Cytoskeleton interacts with extracellular matrix that is attached to the cell (or directly formed by the
  cell). A cell with an oriented cytoskeleton tends to secrete a similarly oriented extracellular matrix,
  which, in turn, influence the orientation of the cytoskeleton in the neighboring cells. A cell's cytoskeleton
  is often organized according to the same pattern in the entire tissue.

Components of the cytoskeleton
 1. protein filaments
        a) actin filaments
        b) intermediate filaments
        c) microtubules
 2. associated proteins
       link filaments to one another or to other cell components (e.g. plasma membrane)
       control assembling of actin filaments and microtubules
       interact with filaments to produce movements
Different types of protein filaments can be identified by their diameter and by the arrangement of their
   protein subunits. Adjacent filaments are often connected by thinner strands.
Actin filaments
Actin is the most abundant protein in eucaryotic cells. In many cells, actin filaments are organized into a
layer under the plasma membrane. Filaments are anchored to plasma membrane and also form a framework
for local specialized structures (microvilli). Similar meshwork, formed by interaction among actin filaments,
microtubules, and intermediate filaments, occurs throughout the cytoplasm. System of actin filaments gives
mechanical strength to the surface and enables the cell to change its shape and to move. Reversible process
of actin polymerization and depolymerization drives many of the surface movements of cells. Interaction
with myosin in the muscle and nonmuscle cells produces sliding movements of the cytoskeleton.
Intermediate filaments
Intermediate filaments are rope-like polymers of fibrous polypeptides that provide a mechanical support to
the cell and its nucleus (e.g. the neurofilaments in the nerve cell axon resist stresses caused by the motion of
the animal).
         A variety of tissue-specific forms are known that differ in the type of polypeptide they contain:
  1. keratin filaments (cytokeratins) are present in epithelial cells, hard keratins are specific to hair and nail
  2. neurofilaments in nerve cells, glial filaments in glia and Schwann cells
  3. desmin filaments of muscle cells

                                                        22
 4. vimentin filaments in fibroblasts
 5. nuclear lamins form a lamina that underlines the nuclear envelope
Microtubules
Microtubules are formed from molecules of tubulin. Cytoplasmic microtubules usually form long filaments,
radiating through cytoplasm from a position close to the nucleus. They provide a system of fibers along
which vesicles and other membrane-bounded organelles can travel. They can also regulate cell shape,
polarity, movement and plane of cell division. Microtubules form a core of cilia and are responsible for the
ciliary movements.
         (In Alzheimer's disease and some other degenerative disorders proteins of neurofilaments appear to
be modified, forming a characteristic lesion called the neurofibrillary tangle. Colchicine inhibits the addition
of tubulin molecules to microtubules, leading to microtubule depolymerization.)
Myosin filaments
Myosin filament is composed of multiple myosin molecules, each consisting of the myosin rod and two
myosin heads. Myosin filament possesses numerous tiny side arms, that extends the head outward to form
cross-bridges with adjacent actin filaments; when a muscle contracts. Myosin molecules can be present in
the form of monomer, dimmer and polymer - a filament.


                 MOLECULAR BASIS OF MOVEMENTS

Actin and myosin interaction
Skeletal muscle consist of regular repeating units - sarcomeres (about 2.5 m long)
each sarcomere contains two sets of parallel and partly overlapping filaments:
     thick filament- extending from one end of the dark band to the other - myosin
     thin filament - extending across each light band and are attached to the two neighboring dark bundles -
         actin
Myosin filament is composed of multiple myosin molecules, each consisting of the myosin rod and two
myosin heads. Myosin filament possesses numerous tiny side arms, that extends the head outward to form
cross-bridges with adjacent actin filaments; when a muscle contracts
Actin filament is a tight helix of actin monomers, with two different protein components: tropomyosin and
troponin. Tropomyosin molecules are wrapped spirally around sides of actin helix. In the resting state the
tropomyosin molecules lie on top of the active sites of actin, so that attraction cannot occur between the actin
and myosin filaments. Molecules of troponin are believed to attach tropomyosin molecules to actin and is
able to bind Ca2+ ions. Actin filament has two different ends: It has a polar structure.
Titin filaments run parallel to the thick and thin filaments and connect the thick filaments to the Z-discs. As
they are very elastic, they are thought to act as springs to help to keep the thick filaments centered between
the Z-discs.
Nebulin is an extraordinary large protein, which is closely associated with the actin thin filaments. It consists
of repeating, 35-amino-acid actin-binding motif that provides a "molecular ruler" to regulate the assembly of
actin and the length of the actin filaments during muscle development.
         ATP is hydrolyzed during muscle contraction. Myosin serves as an actin-activated ATPase.
Efficiency of the conversion of chemical energy to mechanical work is comparatively high (30-50%). ATP
level in an active muscle is regenerated from phosphocreatine.

Sequence of events during the muscle contraction:
         (Sliding model of muscle contraction)
0. Before contraction begins (in the resting stage), the head of myosin binds ATP and hydrolyses it (the
     process is reversible). Liberated energy is stored in myosin head conformation, resulting in an extension
     of head toward the actin filament.
1. Signal for the muscle contraction is an action potential, transmitted from a nerve fiber to the membrane of
     the muscle fiber. This electrical excitation spreads rapidly into series of membranous folds (the
     transverse tubules or T-tubules), that extend inward from the plasma membrane around each myofibril.
2. Voltage changes of the membrane are then transmitted to the sarcoplasmic reticulum
3. Voltage-gated Ca2+ channels in the membrane of sarcoplasmic reticulum are opened and Ca2+ is released
     into the cytoplasm.
4. Calcium ions are bound to a regulating protein troponin, its molecule conforms, relocates molecule of
     tropomyosin and thus "uncovers" the active sites of actin.
5. Myosin head moves to a neighboring actin subunit and binds to it weakly; this triggers the release of
     phosphate, which causes the head to bind very tightly to the actin filament.
6. Once bound, the head undergoes a conformation change generating a "power stroke" that pulls on the rest
     of thick filament.

                                                      23
7. Once the head is tilted, ADP and Pi are released and a fresh molecule of ATP binds to the head, detaching
    the head from the actin filament.
8. The new molecule of ATP is also cleaved and the detached myosin head is carried along the actin filament
    by the action of other myosin heads in the same thick filament. It can bind to other actin subunit and the
    whole cycle repeats. Each myosin head therefore "walks" in a single direction along an adjacent actin
    filament until the Z membrane is pulled up against the ends of the myosin filaments or until the load on
    the muscle becomes to great for further pulling to occur.
9. Higher concentration of calcium ions activates the Ca pump, which starts to transport Ca2+ into the
    sarcoplasmic reticulum or to the extracellular space.
10. Decrease of the calcium concentration reverses the conformation of troponin, restores the position of
    tropomyosin and "cowers" again the active sites of actin.

Relationship between the tension and the length of sarcomere.
        The degree of the overlapping of myosin-actin filaments depends on the actual length of sarcomere,
or on the length of muscle fiber. When the sarcomere shortens and the actin filaments begin to overlap the
myosin filament, the tension increase progressively until the actin filaments has already overlapped all the
cross-bridges of the myosin filament but not yet reached the center of the myosin filament.

Principal types of vertebrate muscles
Skeletal muscle (see above)
Heart muscle has similar structural organization to that of skeletal muscle (striation reflects a very similar
   organization of actin and myosin filaments). However, they differ by presence of intercalated discs.
    1. Intercalated discs attach one cell to the next by means of desmosomes.
    2. They connect the thin filaments of adjacent cells (similarly to Z-discs)
    3. They contain gap junctions, which allow an action potential to spread rapidly from one cell to another.
Smooth muscle cells contain both thick and thin filaments, but these are not arranged in the strictly ordered
   pattern found in skeletal and cardiac muscle. Instead, the filaments form a more loosely arranged
   contractile apparatus, which is roughly aligned with the long axis of the cell, but is attached obliquely to
   the plasma membrane at disclike junctions (dense bodies), serving much the same role as the Z-discs and
   at the same time connecting groups of cells together (gap junctions). Contractile apparatus in smooth
   muscle does not contract as rapidly as the myofibrils in a striated muscle cell, but it permits a much grater
   degree of shortening and therefore can produce large movements. Contraction is triggered by a rise in
   cytosolic Ca2+ but it does not act through troponin-tropomyosin complex. Instead, contraction is initiated
   mainly by phosphorylation of one of the two myosin chains, which in turn control the interaction of
   myosin with actin. Phosphorylation is catalyzed by the myosin kinase and proceeds slowly. Therefore,
   contraction requires nearly a second.
In nonmuscle cells contractile bundles of actin filaments and myosin often assemble for a specific function
   and then disassemble (e.g. belt-like bundle known as the contractile ring during cell division). On the
   contrary, adhesion belts associated with intracellular anchoring the surface of epithelial cells, appear to
   be permanent structures.

Actin filaments based cell movements
         Actin filaments form the plasma membrane skeleton (cell cortex) and participate on the skeleton of
the cell. Approximately 50% of actin molecules are unpolymerized, existing either as free monomers or as
small complexes with other proteins. A dynamic equilibrium exists between unpolymerized actin molecules
and actin filaments. Controlled polymerization at one end, and their breakdown at the other end can push the
plasma membrane, creating cytoplasmic streaming, surface protrusions, exo- and endocytosis or cell
crawling.

Microtubules based movements
Ciliary movements
Cilia are tiny hairlike appendages about 0.25 m in diameter, possessing a microtubular cytoskeleton. Their
   primary function is to move fluid over the surface of the cell or to propel single cell through a fluid. The
   core of a cilium contains nine doublet microtubules arranged in a ring around a central pair of
   microtubules. They are formed from molecules of tubulin and several accessory proteins e.g. dynein,
   which joins neighboring doublets.
The bending force is produced by dynein in a regular cycle of conformation changes driven by ATP binding
   and hydrolysis. Movements of dynein heads along the microtubule cause sliding the doublets against each
   other, similarly to myosin heads walking along the actin filaments. Activation is not based on fluxes of
   Ca2+, but on mechanical movements of neighboring parts of the cilia, to which the movements are
   transmitted from the other parts of cytoskeleton (basal bodies, centriole).

                                                      24
Intracellular transport of organelles and macromolecules
Proteins kinesin and dynein bind particles and certain macromolecules to microtubules and provide the
    propelling force for their anterograde and retrograde movement. They have ATPase activity and may
    form the cross-bridges between the moving organelles, which have the appearance of little feet walking
    along the microtubules (e.g. axonal flow). Kinesin and dynein carry their cargo in opposite directions
    along microtubules. Both types of microtubule motor proteins exist in many forms, each of which
    transports a different cargo.


                 CELL ADHESIONS AND JUNCTIONS

         Most of the cells in multicellular organisms are organized into cooperative assemblies - tissues,
which are in turn associated in various combinations as larger functional units called organs. The cells in
tissues are in direct contact with neighboring cells and very often they are linked to each other at specialized
intercellular junctions. Some part of the cell is usually in contact with a complex network of secreted
extracellular macromolecules, called the extracellular matrix. This matrix helps to hold cells and tissues
together, and it provides an organized lattice within which cells can migrate and interact with one another. In
some cases cells are attached to the matrix at specialized regions of their plasma membrane called cell-
matrix junctions.
         Two extreme examples:
1. Connective tissues - extracellular matrix is plentiful and cells are sparsely distributed within it. The
    matrix, rather than the cells, bears most of the stresses to which the tissue is subjected.
2. Epithelial tissues - cells are tightly bound together into sheets; extracellular matrix is scanty. The cells
    themselves bear most of the stresses by means of strong intracellular protein filaments that criss-cross
    through the cytoplasm of each cell and bind to specialized cell junctions.

        Cell adhesions and junctions
1. Occluding (tight) junctions
   seal cells together in an epithelial cell sheet
   form an anastomosing network of strands that completely encircles the apical end of each cell in the
       epithelial sheet
    functional significance:
     a) inhibit even small molecules from leaking from one side of the sheet to the other (tight junctions in
        the epithelium lining the small intestine are 10 000 times more permeable than those in the
        epithelium of the urinary bladder)
     b) separate fluids of the different composition
     c) block the diffusion of membrane proteins between different cellular domains (basolateral x apical)
2. Anchoring junctions - mechanically attach cells (and their cytoskeletons) to the neighboring cells or to the
         extracellular matrix - prevent separation of cells which are subjected to severe mechanical stress
         (cardiac muscle cells, skin epithelium, smooth muscle cells in the neck of the uterus)
 a. cell to cell adherens junctions - cell to cell connection sites for actin filaments, which run parallel to the
         plasma membrane
           actin bundles are linked via transmembrane glycoproteins (Ca2+ dependent) in a extensive
               transcellular network
           often form a continuous adhesion belt (zonula adherens) around each of the interacting cells
               (epithel cells)
 b. cell to matrix junctions (focal contacts) - connect cells and their actin filaments to extracellular matrix
         (fibroblasts)
 c. desmosomes - intercellular contacts that hold cells together; anchoring sites for intermediate filaments,
         which form a structural framework and provide tensile strength; the particular type of intermediate
         filaments attached to the desmosomes depends on the cell type
             keratin filaments (in most epithelial cells)
             desmin filaments (in heart muscle cells)
             vimentin filaments (in cells that cover the surface of the brain)
 d. hemidesmosomes - connect the basal surface of cells to the underlying basal lamina (extracellular matrix)

3. Communicating junctions
   a. gap junctions - their transmembrane proteins (connexons) of two adjacent cells are aligned thus
      forming a continuous aqueous channel, which connects two cell interiors. At the same time, plasma
      membranes are separated by an interrupted gap. Functional diameter of the channel is about 1.5 nm.
      Gap junctions are dynamic structures that can open and close in response to changes in the cell (Ca2+,

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       voltage, pH, cAMP - e.g. the influx of Ca2+ into a sick or dyeing cell quickly blocks gap junctions of
       such cell, effectively isolating it and thus preventing damage from spreading into neighboring cells).
          allow ions and small water soluble molecules to pass directly from cell to cell
          couple the cells electrically (heart muscle cells, smooth muscle cells responsible for peristaltic
              movements) and/or metabolically (spreading of humoral factors synchronizing the cilia activity
              in epithelial cells)
          in early vertebrate embryos, most cells within one group is coupled together - coupling might
              provide a pathway for humoral factors controlling differentiation (e.g. according to their
              location in the embryo)
   b. chemical synapses
      The principles of chemical communication at a chemical synapse are the same as those of chemical
         communication by water-soluble hormones. Contrary to paracrine communication, messenger
         molecules (neurotransmitters) are released directly to the target cell, they are much less diluted, and
         they diffuse over a very short distance. Because of such organization, transmission is very effective.
      Presynaptic nerve terminal is a characteristic broadening of an axon (most frequently). Both the
         presynaptic and postsynaptic membranes come into close apposition and lie parallel to one another.
         Additional structures stabilize the synaptic association (membrane skeleton + cytoskeleton).
      Action potential that propagate to the presynaptic terminal cause the release of a neurotransmitter by
         exocytosis. The neurotransmitter diffuses across the synaptic cleft (about 50 nm) and binds to a
         specific membrane protein (receptor).
      In channel-linked receptors (ligand-gated channels) it causes a conformation change, which opens
         channel for specific ions and thereby it can alter the membrane permeability very rapidly
         (=postsynaptic potential). Synaptic delay of such synapses is about 0.5 ms.
      Non-channel-linked receptors work by the same mechanisms that mediate responses to water-soluble
         hormones and local chemical mediators. The neurotransmitter-binding site is functionally coupled
         to an enzyme that, in the presence of neurotransmitter, catalyzes the production of an intracellular
         messenger such as cAMP, cGMP, Ca2+, inositoltriphosphate. The intracellular messenger causes
         changes in the postsynaptic cell, including modification of the ion channels in its membrane. The
         response is relatively slow and long in duration (long-lasting neuronal changes linked to learning
         and memory).


                         THE EXTRACELLULAR MATRIX

         A substantial part of the volume in any tissue is constituted by extracellular space, which is largely
filled by a network of macromolecules - the extracellular matrix. Variations and the relative amounts of the
different types of matrix macromolecules and the way they are organized give rise to a diversity of forms and
physical properties adapted to the functional requirements of the particular tissue (e.g. in the connective
tissues the matrix can become calcified to form hard structure of bone, or it can be transparent in cornea). At
the interface between an epithelium and connective tissue, the matrix forms a basal lamina that plays an
important role in controlling cell behavior. The cytoskeleton and extracellular matrix communicate across
the plasma membrane. The cytoskeletons can order the matrix macromolecules the cells secrete, and the
matrix macromolecules can organize the cytoskeletons of cells that contact them.
         The macromolecules that constitute the extracellular matrix are mainly secreted locally by cells in
the matrix (e.g. fibroblasts, chondroblasts):
    a) Polysaccharide glycosaminoglycans (GAGs), usually covalently linked to proteins in the form of
       proteoglycans. Because they form porous hydrated gels they fill most of the extracellular space,
       providing mechanical support to tissues and allowing the rapid diffusion of water soluble molecules
       and the migration of cells.
         aa) hyaluronic acid - increased local production attracts water and thereby swells the matrix to
             facilitate cell migration (inflammation, tissue repair, morphogenesis), joint fluid, vitreous body
         ab) chondroitin sulphate - cartilage, cornea, bone skin, arteries
         ac) heparan sulphate, heparin - lung, arteries, cell surfaces, basal laminae, liver, mast cells
         ad) keratan sulphate - cartilage, cornea, intervertebral disc
    b) Fibrous proteins:
         ba) structural proteins are decisive for the physical properties of the tissue - collagen (strength),
             elastin (resilience)
         bb) adhesive proteins increase attachment to adjacent structures - fibronectin (to the extracellular
             matrix), laminin (attachment of epithelial cells to the basal lamina
         The glycosaminoglycan and proteoglycan molecules form a highly hydrated, gel like "ground
substance" in which the fibrous proteins are embedded. The aqueous phase permits the diffusion of nutrients,
metabolites and signaling molecules between the blood and the tissue cells.

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         The basal lamina - a continuous mat of specialized extracellular matrix that underlies all epithelial
cell sheets and tubes, surrounds individual muscle cells, fat and Schwann cells.
   a) regulates the passage of macromolecules (kidney glomerulus)
   b) acts as a selective cellular barrier (e.g. prevents fibroblasts from making contacts with epithelial cells)
   c) helps regeneration (after injury when epithelial cells are damaged, it provides a scaffolding along
       which regenerating cells can migrate)


                            TISSUE DEVELOPMENT AND MAINTENANCE

Coordination of the cell proliferation is based:
a) Growth factor dependence
b) Anchorage dependence
c) Contact inhibition
d) Limited proliferation capacity

Limits to proliferation
Strategies to protect the organism against the loss of replicative control (against errors in replication,
mutations):
a) the proliferation process is closely tied to apoptosis - cells which lose control normally destroy
    themselves
b) cellular senescence acts as a replicative clock, setting a limit to the number of divisions allowed to a
    non-germline cell

Tissue renewal
Most of the tissues have to replace populations of lost cells, or they have to rebuild their structure as a result
of environmental factors.
1. Tissues with permanent cells
a) Cells generated in embryo and retained through adult life (lens cells)
b) Cells that partly remodel or rebuilt their structure (nerve cells, heart muscle cells)
c) Cells that undergo renewal of their component parts (photoreceptors)
2. Tissues with cell renewal
a) Differentiated cells that divide by the simple duplication (hepatocytes)
b) Cells generated from stem cells (blood cells)

Stem cells
1. Stem cell is not itself terminally differentiated
2. Stem cell divides without limit
3. When stem cell divides, one daughter cell remains a stem cell, the other differentiates to a mature
   functional cell.

Cell Cycle
Produces two genetically identical cells from one precursor cell
G1 and G2 stage - no obvious changes in the nucleus; cells are growing and preparing to divide
S stage - DNA is copied or replicated
M stage - cell divides into two daughter cells

Regulation of cell survival
In many tissues, cells are genetically programmed to die
        if they do not receive specific signals for survival
        if the program is activated by some different specific stimuli
The programmed cell death (apoptosis) is activated during
  a) development of tissues
  b) turnover and renewal of cell populations
  c) as a result of activity changes (hyperactivity or the loss of function)
  d) in pathogenetic conditions (hypoxia, toxic stimuli, in tumors)
apoptosis (=delayed cell death)
   is selective (some cell types are more sensitive - vulnerable)
   it is characterized by distinctive biochemical and morphological features

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  it requires macromolecular synthesis and activation of specific genomic programs
  at the end, cell are phagocytosed by macrophages (or other neighboring cells) without secretion of the
          inflammation-inducing signals
  to activate the disposal mechanism, apoptotic cells change their surface markers

Cell necrosis (=rapid cell death) is the consequence of an acute injury
  swelling
  lysis of cell organelles
  splitting the cytosolic content into the extracellular space
  activation of an inflammatory response




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